CN1081668A - (1 ' R, 3S, 4R) 4-acylthio-azetidinones - Google Patents

(1 ' R, 3S, 4R) 4-acylthio-azetidinones Download PDF

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CN1081668A
CN1081668A CN93107291A CN93107291A CN1081668A CN 1081668 A CN1081668 A CN 1081668A CN 93107291 A CN93107291 A CN 93107291A CN 93107291 A CN93107291 A CN 93107291A CN 1081668 A CN1081668 A CN 1081668A
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compound
formula
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salt
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W·卡布里
I·坎狄尼
A·比迪西
F·扎里尼
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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Priority claimed from GB929226292A external-priority patent/GB9226292D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides a kind of method for preparing the formula I compound, wherein R is H or hydroxyl protecting group, R 2Be a kind of organic residue, R 3Be H or nitrogen-protecting group group.Present method is that the salt one with formula II compound, formula III compound and Ia, IIb family or transition element reacts.The formula I compound is the intermediate of synthetic Penem antibiotic.

Description

(1 ' R, 3S, 4R) 4-acylthio-azetidinones
The present invention relates to a kind of novel method by the synthetic 4-acylthio-azetidinones of 4-acetoxyazetidinone.
As everyone knows, the 4-acylthio-azetidinones is the intermediate of a key in synthetic many useful Penem antibiotic processes, referring to our United States Patent (USP) 4,631,150 and 4,952,577.
These important intermediates prepared in water-bearing media or organic-aqueous medium by 4-acetoxyazetidinone and a suitable thioic acid sulfoacid, but these class methods are not so good usually normally in the presence of alkali, particularly when using responsive thioic acid sulfoacid.And under these conditions, often there are a large amount of impurity, therefore need to increase the step that chromatogram is purified.
The present invention relates to a kind of method, this method provides required mitigation condition to the thioic acid sulfoacid of sensitivity, and obtains the required thioesters that correct structure is arranged (productive rate is up to 95%) of high yield, has only very a spot of by product.And this method is very general, adopts multiple thioic acid sulfoacid all can obtain higher productive rate under the condition of mitigation and safety.
The invention provides a kind of method that is used for preparing the compound of formula I
Wherein R is H or a kind of hydroxy-protective group;
R 2For:
(ⅰ) a kind of straight chain, side chain or cyclic C that is replaced arbitrarily by one or more groups 1-C 6Alkyl, substituting group wherein can be selected from unshielded and protected hydroxyl or amino and alkoxyl group, alkylthio, acyloxy and carbamyl oxygen base or
(ⅱ) a kind of 2-pyridyl or 2-tetrahydrofuran (THF) basic ring or aryl that is replaced arbitrarily by one or more groups, substituting group wherein can be selected from C unshielded and protected hydroxyl or amino and alkoxyl group, acyloxy, carbamyl oxygen base and straight or branched 1-C 4Alkyl, and alkyl itself can be by a kind of unshielded or protected hydroxyl or amino, a kind of alkoxyl group, acyloxy, carbamyl oxygen base replace arbitrarily, or a kind of season derivative that the heterocyclic bases of any replacement is arranged; And R 3Be H or N blocking group.This method is with the compound of formula II and formula III and a kind of II a, and the salt one of II b family or filtration element reacts, and wherein the formula II compound is
Figure 931072913_IMG7
R wherein 1Be a kind of C of straight or branched 1-C 4Alkyl or phenyl, R and R 3Define the samely, the compound of formula III is:
Figure 931072913_IMG8
R wherein 2Define the samely, X is a kind of positively charged ion or siliceous residue.
Obtain at last desirablely having for making (5R, 6S, the Penem nuclear of 1 ' R) steric configuration, the configuration of formula I compound should be 1 ' R, 3S, 4R steric configuration.In one embodiment, a kind of method of the present invention is included in a kind of organic solvent, the formula II and the compound of formula III is in the same place, and then adds described salt.
In another embodiment, method of the present invention is included in the organic solvent, formula III compound and described salt is mixed, and then add formula II compound.
In general, reaction is to carry out in organic solution, and the formula III compound is 1 to 5 molar equivalent, preferably 1 to 3 molar equivalent.The consumption of II a, II b family or transition element salt generally is 0.1 to 5 molar equivalent, preferably 0.1 to 3 molar equivalent.Temperature of reaction generally is-20 ℃ to 60 ℃, preferably 0 ℃ to 40 ℃.General 1 hour to 3 days of reaction times, preferably 4 hours to 1 day.
The C of straight or branched 1-C 6Alkyl generally is the C of straight or branched 1-C 4Alkyl, these C 1-C 4The example of alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl and the tertiary butyl, particularly methyl or ethyl.
What R was best is H or a kind of hydroxyl protecting group.
R 2Best is:
(ⅰ) by a kind of unshielded or protected hydroxyl or amino, or a kind of straight chain, side chain or cyclic C 1-C 4Alkoxyl group, alkylthio or C 1-C 5Alkanoyloxy, or any C that replaces of a kind of carbamyl oxygen base 1-C 4Alkyl group;
(ⅱ) 2-tetrahydrofuran base or the 2-pyridyl that is replaced arbitrarily by one or more groups, wherein substituted radical is selected from unshielded and protected hydroxyl and amino and alkoxyl group and acyloxy;
(ⅲ) phenyl ring that is replaced by one or more groups, wherein substituted radical is selected from a kind of unshielded or protected hydroxyl, a kind of usefulness unshielded or protected hydroxyl or the amino C that replaces arbitrarily 1-C 4Alkyl or the season derivative of the heterocyclic bases of any replacement is arranged.Be suitable for season derivative example comprise tetramethyleneimine and pyridine group.
Work as R 2C for a kind of straight or branched of replacement 1-C 4During alkyl, substituting group preferably is selected from carbamyl oxygen base, acetoxyl group, methoxyl group, unshielded or protected hydroxyl, and unshielded or protected amino.Work as R 2When being a kind of 2-pyridyl of any replacement, its preferably unsubstituted 2-pyridyl or the 2-pyridyl that is replaced by one or more unshielded or protected hydroxyl.Work as R 2When being a kind of unsubstituted 2-tetrahydrofuran base, its unsymmetrical carbon is the R configuration.
R 2Group is carbamyl oxygen methyl preferably, acetyl-o-methyl, methoxyl methyl, unshielded or protected hydroxyl, 2-tetrahydrofuran base and unshielded or protected amino methyl.Work as R 3When rolling into a ball for nitrogen-protecting group, it preferably is selected from tertiary butyl dimethyl, trimethyl silyl C 1-C 4Alkyl and triethylsilyl.
When mentioned hydroxyl or amino the need when protected; available any known group of protection hydroxyl or amino part that is applicable to is protected; these blocking groups preferentially are selected from t-butyldimethylsilyl, trimethyl silyl, triethylsilyl, pyranyl, acyl group, p-nitrophenyl oxygen carbonyl and 2; 2, the 2-trichloro-ethoxycarbonyl.
When the X group is represented a kind of positively charged ion, preferably a kind of basic metal or alkaline earth metal cation, ammonium ion or trialkyl ammonium or tetraalkyl ammonium cation.X is sodium preferably, potassium or trialkyl ammonium cation.
X makes formula III compound become activity form as active residue, then can be in replacing the formula II compound-OCOR 1Group.When X was siliceous residue, it generally was one SiR ' R " R ' ", and wherein R ', R ", R ' " are respectively the C of straight or branched 1-C 4Alkyl group, SiR ' R " R ' " preferred examples is trimethyl silyl and t-butyldimethylsilyl group.
II a, preferably a kind of halogenide of the salt of II b family or transition element (as muriate, bromide or iodide) or a kind of carboxylicesters (as acetic ester), or a kind of inorganic anionic salt (as carbonate) arranged.II a family element is Mg preferably, and II b family element is Zn preferably.
Transition element is meant first and second or triplex row transition element, generally is the first row transition element.It preferably is selected from Fe, Co and Ni.Preferably a kind of three iron halide of the salt of transition element are as FeCl 3, FeBr 3Or FeI 3
The organic solvent that is fit to comprises polar solvent such as acetonitrile, tetrahydrofuran (THF), diox, glycol dimethyl ether, ethyl acetate and their mixture, preferred solvent Shi diox, tetrahydrofuran (THF), glycol dimethyl ether and ethyl acetate.
If necessary, II a, the salt of II b family or transition element can be separated repeated use with ordinary method from reaction medium, for example can adopt and filter or the water method of extraction, reclaims original salt then.
If the above-mentioned thioic acid sulfoacid that use to be fit to contain silicon derivative the time, for example the X in formula III is that the described salt of a kind of siliceous residue can use (for example 10% of the feed molar number to 20%) by catalytic amount arbitrarily.
Formula III compound and described salt mix in organic solvent, can form a kind of mixture with the reaction of formula II compound then.
The starting compound of formula II is that known compound and some are commercially available product.
Can there be two kinds of isomer in the formula II compound, i.e. 1 ' R, and 3R, 4R and 1 ' R, 3R, the 4S isomer, and two kinds of isomer or their mixture all can be used as raw material.
The formula III compound is known, or the preparation of available currently known methods.
Because reagent is cheap, and the productive rate height, easy and demulcent reaction conditions, therefore method of the present invention is specially adapted to mass preparation formula I compound.
As mentioned above, the formula I compound is the intermediate of a key in synthetic many useful Penem antibiotic, and therefore method of the present invention is especially for the suitability for industrialized production of Penem antibiotic.
In one embodiment, method of the present invention comprises increases a step that the formula I compound is changed into a kind of Penem antibiotic.For example prepared Penem antibiotic can be with following formula (I a) compound or their pharmaceutical salts:
R in the formula 2' be carbamyl oxygen methyl, methoxyl methyl or 2(R) tetrahydrofuran base, R 4' be hydrogen atom, acetyl-o-methyl or (5-methyl-2-oxygen-1,3 dioxy cyclopentenes-3-yl) methyl.
The formula I compound changes into Penem antibiotic suc as formula (the I a) reaction of compound can adopt the ordinary method of being familiar with to carry out in the Penem compound chemistry.Conversion reaction generally comprises cyclization and removes the blocking group of being deposited arbitrarily.Also can further comprise optional optical resolution reaction or introduce a substituting group forming ester group on 3 of Penem nuclear, for example (I a) is introduced R in the compound in above-mentioned formula 4' group.
Resulting Penem antibiotic, (I a) compound can further change into a kind of their salt salt to for example a kind of formula when needed.
Therefore (I a) compound or its pharmaceutical salts subsequently can be formulated together with a kind of pharmaceutical carrier or thinner for for example a kind of formula of Penem antibiotic.The pharmaceutical composition that obtains can oral or parenteral administration.
The following examples will further specify method of the present invention.
Embodiment 1
4(R)-carbamyl oxygen acetylthio-3-(S)-(1-(R)-t-butyldimethylsilyloxy ethyl) nitrogen heterocyclic din-2-ketone
To 4-(R) acetoxy-3 (R)-(1(R) t-butyldimethylsilyloxy ethyl) nitrogen heterocyclic din-2-ketone (2.87g) adds carbamyl oxygen thioacetic acid sylvite (2.1g) in the solution of diox (40ml).In the suspension that obtains, add zinc bromide (2.7g), and under 40 ℃, reaction mixture was stirred 4 hours.Then reaction mixture is chilled to room temperature, and pours in the mixture of ethyl acetate and water.Tell organic phase, wash twice with water, through anhydrous sodium sulfate drying, vacuum-evaporation.Solid residue CH 2Cl 2Absorb.Add hexane and cooling, separate out white solid.Filter to collect and obtain 3.26g title compound product (productive rate 90%).
NMR（CDCl 3）δ（ppm）：0.1（6H，s）;0.75（9H，s）;1.18（3H，d）;3.18（1H，dd）;4.23（1H，m）;4.75（2H，ABq）;5.35（1H，d）;5.45（2H，br s）;7.05（1H，s）
Embodiment 2
4(R)-carbamyl oxygen acetylthio-3(S)-(1(R)-t-butyldimethylsilyloxy ethyl) nitrogen heterocyclic din-2-ketone
Reaction is undertaken by embodiment 1 described method, be used solvent be ethyl acetate.React 3 hours postcooling.After routine operation and crystallization, obtain the title product of 85% productive rate.
Embodiment 3
4(R)-carbamyl oxygen acetylthio-3(S)-(1(R)-t-butyldimethylsilyloxy ethyl) nitrogen heterocyclic din-2-ketone
Reaction is undertaken by embodiment 1 described method, and just reaction is at room temperature to carry out 8 hours.After routine operation and crystallization, obtain the title product of 90% productive rate.
Embodiment 4
4(R)-and the t-butyldimethylsilyloxy ethyl of carbamyl oxygen acetylthio-3(S)-(1(R)) nitrogen heterocyclic din-2-ketone
Reaction is undertaken by the method described in the embodiment of front, just uses zinc chloride instead.After routine operation and crystallization, obtain the title product of 75-80% productive rate.
Embodiment 5
4(R)-and the t-butyldimethylsilyloxy ethyl of carbamyl oxygen acetylthio-3(S)-(1(R)) nitrogen heterocyclic din-2-ketone
Reaction is undertaken by the method described in the embodiment of front, just uses magnesium chloride instead.After routine operation and crystallization, obtain the title product of about 50% productive rate.
Embodiment 6
4(R)-and the t-butyldimethylsilyloxy ethyl of methoxy acetylthio-3(S)-(1(R)) nitrogen heterocyclic din-2-ketone
Reaction is undertaken by the method for previous embodiment, just uses iron trichloride (1.5 equivalent) instead.After routine operation and crystallization, obtain the title product of 60% productive rate.
Embodiment 7
4(R)-and the t-butyldimethylsilyloxy ethyl of carbamyl oxygen acetylthio-3(S)-(1(R)) nitrogen heterocyclic din-2-ketone
React by embodiment 1 described method, just use 2.6g raw material thiosalt and 3.4g zinc bromide instead.Heated 1.5 hours and routine operation and crystallization after, obtain the title product of 95% productive rate.
Embodiment 8
4(R)-and the t-butyldimethylsilyloxy ethyl of methoxy acetylthio-3(S)-(1(R)) nitrogen heterocyclic din-2-ketone
To 4-(R) acetoxy-3 (R)-(1(R) t-butyldimethylsilyloxy ethyl) ring fourth-2-ketone (adding methoxyl group thioacetic acid potassium (1.7g) in the solution of 2.87g) Zai diox (40ml).Add zinc bromide (2.7g) in the suspension that obtains, reaction mixture stirred 4 hours down at 40 ℃.Then reaction mixture is chilled to room temperature and pour ethyl acetate into and the mixture of water in.Tell organic phase, wash with water twice.Through anhydrous sodium sulfate drying, vacuum-evaporation.Residue is purified with column chromatography, obtains 2.99g title product (productive rate 90%).
NMR（CDCl 3）δ（ppm）：0.1（6H，s）;0.83（9H，s）;1.16（3H，d）;3.13（1H，dd）;3.42（3H，s），4.01（2H，s）4.20（1H，m）;5.22（1H，d）;6.55（1H，s）
Embodiment 9
4(R)-acetylthio-3(S)-(1(R)-t-butyldimethylsilyloxy ethyl) nitrogen heterocyclic din-2-ketone
To 4-(R) acetoxy-3 (R)-(1(R) t-butyldimethylsilyloxy ethyl) nitrogen heterocyclic din-2-ketone (adds sodium thioglycolate (1.2g) in the solution of 2.87g) Zai diox (40ml).In the suspension that obtains, add zinc bromide (2.7g), and reaction mixture was stirred 4 hours down at 40 ℃.Then reaction mixture is chilled to room temperature, pours in the mixture of ethyl acetate and water.Tell organic phase, wash twice with water, through anhydrous sodium sulfate drying, vacuum-evaporation.Residue obtains 2.7g title product (productive rate 89%) after purifying with column chromatography.
NMR（CDCl 3）δ（ppm）：0.1（6H，s）;0.86（9H，s）;1.19（3H，d）;2.37（3H，s）;3.14（1H，dd）;4.24（1H，m）;5.31（1H，d）;6.31（1H，s）.
Embodiment 10
4(R)-(4-(tert-butyl diphenyl silicomethane oxygen methyl) the t-butyldimethylsilyloxy ethyl of benzoyl sulfenyl-3(S)-(1(R))) nitrogen heterocyclic din-2-ketone
To 4-(R) acetoxy-3 (R)-(1(R) t-butyldimethylsilyloxy ethyl) nitrogen heterocyclic din-2-ketone (adding (4-(tert-butyl diphenyl silicomethane oxygen methyl) in the solution in the 2.87g) Zai diox (40ml)) thiobenzoic acid potassium (4.99g).In the mixture that obtains, add zinc chloride (1.64g).This reaction mixture stirred 4 hours down at 40 ℃.Then it is chilled to room temperature and pour ethyl acetate into and the mixture of water in.Tell organic phase, wash twice with water, through anhydrous sodium sulfate drying, vacuum-evaporation.Residue is purified with column chromatography and is obtained 5.13g title product (productive rate 85%).
Embodiment 11
4(R)-and the t-butyldimethylsilyloxy ethyl of nicotinoyl sulfenyl-3(S)-(1(R)) nitrogen heterocyclic din-2-ketone
To 4-(R) acetoxy-3 (R)-(1(R) t-butyldimethylsilyloxy ethyl) nitrogen heterocyclic din-2-ketone (adding sulfo-naotin (1.94g) in the solution in the 2.87g) Zai diox (40ml).(1.7g) joins in the mixture of generation with zinc chloride, and reaction mixture was at room temperature stirred 4 hours.Then reaction mixture is chilled to room temperature, and pours in the mixture of ethyl acetate and water.Tell organic phase, wash twice with water, through anhydrous sodium sulfate drying, vacuum-evaporation. residue is purified with column chromatography and is obtained 1.9 title product (productive rate 52%).
Embodiment 12
4(R)-and the t-butyldimethylsilyloxy ethyl of carbamyl oxygen acetylthio-3(S)-(1(R)) nitrogen heterocyclic din-2-ketone
Reaction is undertaken by embodiment 1 described method, just uses carbamyl oxygen thioacetic acid triethylamine (3.04g) instead.React 4 hours postcooling, after routine operation and crystallization, obtain the title compound of 90% productive rate.
Embodiment 13
4(R)-and the t-butyldimethylsilyloxy ethyl of methoxyl group acetylthio-3(S)-(1(R)) nitrogen heterocyclic din-2-ketone
Reaction is undertaken by embodiment 8 described methods, just uses methoxyl group thioacetic acid (1.4g) instead, and adds triethylamine (1.82ml) in reaction mixture.React 4 hours postcooling, after routine operation and crystallization, obtain the title product of 90% productive rate.
Embodiment 14
4(R)-and the t-butyldimethylsilyloxy ethyl of carbamyl oxygen acetylthio-3(S)-(1(R)) nitrogen heterocyclic din-2-ketone
Reaction is undertaken by embodiment 1 described method, and derivative (5.6g) and the 0.32g zinc bromide of just using the thiacetic trimethyl silyl of carbamyl oxygen base instead react in acetonitrile.At room temperature stirring 15 hours afterreactions carries out according to a conventional method.Obtain the title product of 70% productive rate.
Embodiment 15
4(R)-and the t-butyldimethylsilyloxy ethyl of carbamyl oxygen acetylthio-3(S)-(1(R)) nitrogen heterocyclic din-2-ketone
Reaction is undertaken by embodiment 1 described method, just uses zinc iodide instead.After routine operation and crystallization, obtain the title product of 80% productive rate.
Embodiment 16
4(R)-and the t-butyldimethylsilyloxy ethyl of carbamyl oxygen acetylthio-3(S)-(1(R)) nitrogen heterocyclic din-2-ketone
Reaction is undertaken by embodiment 1 described method, is raw materials used for 4(R and S) acetoxy-3 (R)-(1(R) t-butyldimethylsilyloxy ethyl) mixture of nitrogen heterocyclic din-2-ketone.Obtain the title product of 88% productive rate.
Embodiment 17
4(R)-(2-tetrahydrofuran (THF) acyl sulfenyl-3(S)-(1(R) t-butyldimethylsilyloxy ethyl) nitrogen heterocyclic din-2-ketone
To 4(R)-acetoxy-3 (R)-(1(R) t-butyldimethylsilyloxy ethyl) nitrogen heterocyclic din-2-ketone (adds tetrahydrofuran (THF)-2-thiocarboxylic acid potassium (2.1g) in the solution of 2.87g) Zai diox (40ml).Add zinc bromide in the suspension that obtains, this reaction mixture stirred 6 hours down at 35 ℃.Behind routine operation, obtain the title product of 92% productive rate.
MNR（CDCl 3）δ（ppm）：1.19（d，1.5H），1.21（d，1.5H），1.82-2.40（m 4H），3.15-3.20（m，1H），3.90-4.13（m，2H），4.17-4.33（m，1H），4.48（dd，1H），5.18（d，0.5H），5.23（d，0.5H），6.28（d，1H）.

Claims (13)

1, a kind of be used for the preparation have 1 ' R, 3S, the method for the formula I compound of 4R configuration,
Wherein R is H or a kind of hydroxy-protective group;
R 2For
(ⅰ) a kind of straight chain, side chain or cyclic C that is replaced arbitrarily by one or more groups 1-C 6Alkyl, these substituting groups are selected from unshielded or protected hydroxyl or nitrogen base, and alkoxyl group, alkylthio, acyloxy and carbamyl oxygen base or
(ⅱ) a kind of 2-pyridyl or 2-tetrahydrofuran (THF) basic ring or aryl that is replaced arbitrarily by one or more groups, these substituting groups are selected from unshielded or protected amino and hydroxyl, and the C of alkoxyl group, acyloxy, carbamyl oxygen base and straight or branched 1-C 4Alkyl, and alkyl itself can replace arbitrarily by unshielded or protected hydroxyl or amino, alkoxyl group, acyloxy, carbamyl oxygen base, or a kind of season derivative of heterocyclic bases of any replacement;
R 3Be hydrogen or a nitrogen-protecting group group, this method comprises that the salt one with formula II compound, formula III compound and II a, II b family or transition element reacts,
Formula II compound
Figure 931072913_IMG3
R wherein 1Be the C of straight or branched 1-C 4Alkyl or phenyl, R and R 3Definition the same;
The formula III compound
Figure 931072913_IMG4
R wherein 2Definition is the same, and X is a positively charged ion or a siliceous residue.
2, comprise formula II compound or formula III compound are mixed in organic solvent according to the process of claim 1 wherein, and then add described salt.
3, comprise formula III compound and described salt are mixed in organic solvent according to the process of claim 1 wherein, and then add the formula II compound.
4, according to each method in the claim 1 to 3, wherein be reflected in the organic solvent and carry out, the molar equivalent of formula III compound is 1 to 5, and the molar equivalent of described salt is 0.1-5, and temperature of reaction is from-20 ° to 60 ℃, and the reaction times was from 1 hour to 3 days.
5, according to any one method in the claim 1 to 4, wherein this method is carried out in being selected from acetonitrile, tetrahydrofuran (THF), diox, dimethoxy ethane, ethyl acetate and composition thereof.
6, according to any one method in the aforementioned claim, wherein said salt is a kind of Zn salt, Mg salt or Fe salt.
7, according to any one method in the aforementioned claim, wherein said salt is a kind of halogenide, acetic ester or carbonic ether.
8, according to any one method in the aforementioned claim, wherein R is H or hydroxy-protective group, R 2For
(ⅰ) a kind of C of straight or branched 1-C 4Alkyl group, it can be replaced arbitrarily by following radicals: unshielded or protected amino or hydroxyl, straight chain, side chain or cyclic C 1-C 4Alkoxyl group, alkylthio or C 1-C 5Alkanoyloxy, or carbamyl oxygen groups;
(ⅱ) be selected from unshielded or protected hydroxyl and amino by one or more, and alkoxyl group and any 2-pyridyl or the 2-tetrahydrofuran base that replaces of acyloxy;
(ⅲ) a kind of benzyl ring that is replaced arbitrarily by one or more groups, substituting group is selected from unshielded or protected hydroxyl, the C of straight or branched 1-C 4Alkyl, alkyl also can be replaced or have the season derivative of the heterocyclic bases of any replacement by unshielded or protected hydroxyl or amino group arbitrarily;
R 3Definition described identical with claim 1;
X is a kind of basic metal or alkaline earth metal cation, ammonium cation, trialkyl or tetraalkylammonium cation or trimethyl silyl or t-butyldimethylsilyl.
9, according to the method for claim 8, R wherein 2For
(ⅰ) a kind of by the C of any straight or branched that replaces of following groups 1-C 4Alkyl, carbamyl oxygen base, acetoxyl group, methoxyl group, unshielded or protected hydroxyl, perhaps unshielded or protected amino group; Or
(ⅱ) a kind of unsubstituted 2-pyridyl or a kind of 2-pyridyl that unshielded or protected hydroxyl replaces by one or more;
(ⅲ) a kind of unsubstituted 2-tetrahydrofuran base with R configuration unsymmetrical carbon.
10, according to any one method in the aforementioned claim, comprising the step that the formula I compound is changed into Penem antibiotic.
11, according to the method for claim 10, Penem antibiotic wherein is that (I is compound or their pharmaceutical salts a) for following formula.
Figure 931072913_IMG5
R wherein 2' be carbamyl oxygen methyl, methoxyl methyl or 2(R) tetrahydrofuran base, R 4' be hydrogen atom, acetyl-o-methyl or (5-methyl-2-oxygen-1,3-dioxy cyclopentenes-3-yl) methyl.
12, a method according to claim 11 is comprising by cyclization the formula I compound being transformed an accepted way of doing sth (I Penem a); Remove the blocking group of any one existence; The optical resolution of choosing wantonly, or the radicals R of introducing and the same definition of claim 11 4'; When needed, also can (I a) compound changes into their pharmaceutical salts with the formula that obtains.
13, according to any one method in the claim 10 to 12, comprising further with the step of Penem antibiotic and pharmaceutical carrier or thinner preparation.
CN93107291A 1992-06-16 1993-06-14 (1 ' R, 3S, 4R) 4-acylthio-azetidinones Pending CN1081668A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9212707.5 1992-06-16
GB929212707A GB9212707D0 (en) 1992-06-16 1992-06-16 4-acylthio azetidiones
GB929226292A GB9226292D0 (en) 1992-12-17 1992-12-17 (1,3,3s,4r)4-acylthio azetidinones
GB9226292.2 1992-12-17

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GB8321677D0 (en) * 1983-08-11 1983-09-14 Erba Farmitalia Preparation of penems
EP0215739B1 (en) * 1985-09-11 1993-09-01 Ciba-Geigy Ag Synthesis of beta-lactam compounds
US4782145A (en) * 1986-06-02 1988-11-01 Pfizer Inc. Process for penem derivatives
GB8713515D0 (en) * 1987-06-10 1987-07-15 Erba Farmitalia Methoxymethyl compounds
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JPH06509818A (en) 1994-11-02
EP0574784B1 (en) 2001-12-05
ATE210115T1 (en) 2001-12-15
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AU666559B2 (en) 1996-02-15
DE69331249T2 (en) 2002-06-13
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